title: A kinetic method for the determination of plasma protein binding of compounds unstable in plasma: Specific application to enalapril.
abstract: Traditional methods for the determination of plasma protein binding (PPB), such as equilibrium dialysis and ultrafiltration, normally operate on a timescale ranging from tens of minutes to several hours and are not suitable for measuring compounds that have significant chemical degradation on this timescale. One such compound is enalapril. Although stable in human plasma enalapril is subject to rapid esterase-catalyzed hydrolysis in rat plasma. A method has been developed which allows the extent of rat PPB of enalapril to be determined from initial rates kinetics of the adsorption of the unstable compound to dextran coated charcoal (DCC). The method has been applied to stable compounds, and the results are consistent with those from traditional equilibrium dialysis experiments. The experimental method is simple to run, requires no specialized equipment, and can potentially be applied to other compounds that show instability in plasma where traditional experimental techniques are unsuitable.
authors.affiliation: Department of Medicinal Chemistry, AstraZeneca R&D Charnwood, Loughborough LE11 5RH, UK. mark.wenlock@astrazeneca.com
authors.forename: Mark C
authors.initials: MC
authors.lastname: Wenlock
authors.forename: Patrick
authors.initials: P
authors.lastname: Barton
authors.forename: Rupert P
authors.initials: RP
authors.lastname: Austin
mesh_terms: D000327:Adsorption; D000818:Animals; D001798:Blood Proteins / Q000737:chemistry / Q000378:metabolism*; D002498:Centrifugation; D002606:Charcoal / Q000737:chemistry; D019411:Clinical Laboratory Techniques / Q000295:instrumentation; D003911:Dextrans / Q000737:chemistry; D003956:Dialysis; D004285:Dogs; D004355:Drug Stability; D004656:Enalapril / Q000737:chemistry / Q000378:metabolism*; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D010879:Piperazines / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D011687:Purines / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D015203:Reproducibility of Results; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000737:chemistry / Q000378:metabolism; D013997:Time Factors; D014700:Verapamil / Q000737:chemistry / Q000378:metabolism; D014859:Warfarin / Q000737:chemistry / Q000378:metabolism
chemical_list: D001798:Blood Proteins; D003911:Dextrans; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D002606:Charcoal; D014859:Warfarin; D004656:Enalapril; D000068677:Sildenafil Citrate; D014700:Verapamil